It has been postulated that the activities of certain enzymes may be markers of a genetic predisposition to alcoholism. We previously showed that low fluoride-stimulated platelet adenylate cyclase (AC) activity, and an increased sensitivity of platelet monoamine oxidase (MAO) to in vitro inhibition by ethanol, effectively discriminated alcoholic and non-alcoholic individuals. We have now examined the heritability of platelet fluoride-stimulated AC activity in families with alcoholic members, and have found familial transmission, with a major gene effect, for this enzyme activity. The major gene was transmitted as a Mendelian co- dominant. Transmission of basal AC activity was more complex. The findings are compatible with the possibility that fluoride-stimulated AC activity, which is transmitted as a single major gene in families of alcoholics, could represent a trait marker for a predisposition to alcoholism. AC activity was also assayed in platelets of monozygotic and dizygotic twins and concordance was higher in monozygotic twins, supporting the heritability of this measure. Platelet fluoride-stimulated AC activity is currently being compared with several other possible genetic markers of predisposition to alcoholism. Previous Western and slot blot analysis showed that the total quantity of G(S-alpha) in platelet membranes was not significantly correlated with fluoride-stimulated AC activity. Recent data indicates that there is a significant positive correlation of stimulated AC activity and cholera toxin-induced ADP-ribosylation. These results suggest that a qualitative, rather than a quantitative, difference in G(S-alpha) may contribute to lower platelet AC activity in alcoholics. The studies described will help to determine whether the observed differences in platelet enzyme activities between alcoholics and non-alcoholics are genetically based, and may be a marker for a predisposition to alcoholism, or are a consequence of ethanol consumption.